European Bioanalysis Forum

Transcription

1 European Bioanalysis Forum Alternative Approaches for Assessment of Drug Neutralizing Activity of ADA Responses Presenter: Arjen Companjen (on behalf of EBF topic team 19) EIP meeting Lisbon 25 February 2014

2 EBF: who we are, what we do EBF: European Bioanalysis Forum Founded: 2006 as an initiative of 12 pharmaceutical companies with bioanalytical lab activities in Europe The goal of forming our Forum was to create a platform for discussions of science, day-to-day procedures, business tools, technologies and last but not least regulatory issues Today, EBF counts >50 company members, or the vast majority of Pharma companies and CRO (global and EU based) with regulated bioanalysis activities in EU 18/03/

3 EBF: organization and structure EBF core: All EBF core members chaired by a steering committee of 6 members Small Molecules (SMOL) Interest Group Large Molecules (IGM) Topic Teams (TT) discussing small molecule subjects Topic Teams (TT) discussing general subjects Topic Teams (TT) discussing large molecule subjects 18/03/

4 EBF Mission In Topic Teams we share, discuss, optimize and seek alignment on a broad array of bioanalytical topics including science, procedures, business tools and technology, and regulatory issues 18/03/

5 EBF: organization and structure EBF core: All EBF core members chaired by a steering committee of 6 members Small Molecules (SMOL) Interest Group Large Molecules (IGM) Topic Teams (TT) discussing small molecule subjects Topic Teams (TT) discussing general subjects Topic Teams (TT) discussing large molecule subjects Output: Commenting on draft guidelines (e.g. FDA, EMA, MHLW BMV guidelines) Discuss their topic at the EBF annual meeting in Barcelona or at EBF workshops Produce white papers 18/03/

6 EBF Mission In Topic Teams we share, discuss, optimize and seek alignment on a broad array of bioanalytical topics including science, procedures, business tools and technology, and regulatory issues We aim to recommend or influence opinions/procedures towards our members, business partners, regulatory bodies and any other stakeholders Going forward, EBF is providing consolidated assistance and recommendations to the European and Global bioanalytical community Finally, support development opportunities for EU based scientists by joining cross company collaborations and contributions to peer reviewed journals, international meetings and symposia 18/03/

7 EBF Topic Team-19 EBF core: All EBF core members chaired by a steering committee of 6 members Interest Group Large Molecules (IGM) Topic Teams (TT) discussing large molecule subjects TT-19: Alternatives for the characterization of ADA neutralizing antibodies 18/03/

8 Assessment of ADA responses: What do we have to do and what is in the guidelines Identification and characterization of ADA responses requires a detailed program during development of therapeutic proteins For identification of ADA in clinical studies a screening and confirmatory assay should be in place The procedure for characterization of ADA is described in guidelines of FDA and EMA The development of a neutralizing Ab assay (NAb-assay) is recommended: 18/03/

9 Assessment of ADA responses: What do we have to do and what is in the guidelines EMA guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins: FDA draft guideline for assay development for immunogenicity testing of therapeutic proteins: 18/03/

10 Assessment of ADA responses: What do we have to do and what is in the guidelines EMA guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use: 18/03/

11 Assessment of ADA responses: What do we have to do and what is in the guidelines Identification and characterization of ADA responses requires a detailed program during development of therapeutic proteins For identification of ADA in clinical studies a screening and confirmatory assay should be in place The procedure for characterization of ADA is described in guidelines of FDA and EMA The development of a neutralizing Ab assay (NAb-assay) is recommended During this session we would like to discuss alternative approaches for the assessment of NAb activity of ADA 18/03/

12 PD and PK units Are there alternative ways to assess ADA NAb responses? PK/PD profiles may be used to identify the neutralizing effect of an ADA response PD ADA+ subject PD mean PK ADA+ subject PK mean Study day Please note: simulated example Can we use PK/PD profile analysis as an alternative to the assessment of NAb activity by means of a NAb-assay? 18/03/

13 Are there alternative ways to assess ADA NAb responses? To investigate the use of the PK/PD approach at EBF member companies we performed two surveys First survey: Insight into approach of ADA NAb assessment by different EBF pharma companies developing biotherapeutics Second survey: More specific on PK/PD analysis in HAHA positive subjects and comparison with NAb assessment (MAb products) 18/03/

14 Approach of ADA NAb assessment by different EBF pharma companies First survey: out of the then ~37 EBF-IGM companies, 10 (i.e. 27%) answered the survey questions All companies start ADA assessments already during pre-clinical phase Low-risk protein: some companies perform NAb-assays in Phase-II while others start to develop those by Phase-III High-risk protein: all companies perform NAb-assays during all phases and during pre-clinical on case-by-case basis Some companies have a strategy in place and some do a case-by-case decision which depends on the drug, extent of the immune response and adverse events All companies investigate PK/PD profiles of ADA + subjects and compare these with ADA - subjects. Implementation of cellular or competitive ligand binding assay is a case-by-case decision 18/03/

15 The case of the high and low risk molecules With high and low risk we do not mean overall risk but only in respect of effect of anti-drug NAb-responses Risk analysis determines the molecule to be of high risk : Consequence of a neutralizing ADA response: - Impaired efficacy - Impact on safety (neutralization of the endogenous counterpart(s)) Required actions: - PK/PD read-out - NAb-assays to detect neutralizing antibodies against: -- the drug, -- the endogenous counterpart -- and if nessessary against endogenous protein very similar to drug 18/03/

16 The case of the high and low risk molecules With high and low risk we do not mean overall risk but only in respect of effect of anti-drug NAb-responses Risk analysis determines the molecule to be of low risk : Main consequence of neutralizing ADA response: - Impaired efficacy - No direct impact on safety Loss of efficacy might be self evident through low patient response and a PD read-out may be considered the most biologically relevant neutralizing assay If this is not feasible, the use of target binding inhibition assays (competitive ligand binding assays) for antagonistic MAb drugs and the use of cellular assays for agonistic MAb drugs are recommended Focus of second survey: MAb-drugs (i.e. HAHA responses) 18/03/

17 Approach of HAHA NAb assessment by different EBF pharma companies Second survey: Focus on MAb-drugs (i.e. HAHA responses) 15 pharma/cro companies of the EBF-IGM companies answered the questions (compared to the 1 st survey EBF was enlarged and now included CRO as well) 60% perform assessment of PK/PD profiles (even when there is a NAb-assay in place) Comparison of PK/PD profiles of HAHA + vs. HAHA - subjects was done by 40% of the companies In most of the studies NAb-data correlate with the PK/PD data For 43% of the companies NAb-assays were not sensitive enough to detect NAb-activity of HAHA 18/03/

18 Points for discussion PD assays are usually more sensitive than NAb-assays and as a consequence better for analysis of neutralizing ADA responses A decrease in PK/PD levels in ADA + subjects imply occurrence of NAb Safety markers should be included when replacing NAb-assays by PK and PD markers In vitro Screening Screening Confirmatory Clinical relevance assessment Safety ADA specific AE s? AE analysis in ADA+ group vs ADA-group Efficacy PK/PD analysis in ADA+ group vs ADA-group Safety prompted characterisation Efficacy prompted characterisation 18/03/

19 Points for discussion PD assays are usually more sensitive than NAb-assays and as a consequence better for analysis of neutralizing ADA responses A decrease in PK/PD levels in ADA + subjects imply occurrence of NAb Safety markers should be included when replacing NAb-assays by PK and PD markers NAb-assays are not sensitive enough and are prone to drug interference Do we agree that for low risk molecules PK/PD assessment is enough? How should we discriminate low from high risk molecules? What kind of PD assay could replace NAb-assays? What do the regulators expect from us and what are our experiences? 18/03/

20 Acknowledgements EBF TT-19 team: Inge Dreher (AbbVie) Martin Nemansky (PRA) Craig Stovold (Quotient Bio Analytical Sciences) Denise Sickert (Novartis) Yvonne Katterle (Bayer Pharma AG) Edwin Janssen (Eurofins) Margarete Brudny-Klöppel (Bayer Pharma AG and sponsor) All EBF-IGM members involved in the discussion 18/03/